Pregnancy-associated plasma protein-A (PAPP-A) is a zinc-binding matrix metalloproteinase that regulates extracellular matrix remodeling. PAPP-A degrades IGFBP-4, increasing levels of local IGF-1 in response to injury, and could be involved in the pathogenesis of atherosclerosis (1–6). Inflammatory cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-1β, implicated in insulin resistance (7), are potent stimulators of PAPP-A (8,9). The association between PAPP-A levels and metabolic parameters such as cholesterol and high-sensitivity C-reactive protein (hsCRP) is controversial (2,10,11). We aimed to study the relationship between PAPP-A, glycemic control and other metabolic and hemostatic parameters, inflammatory cytokines, and ankle-brachial pressure index (ABI) in diabetic patients.

Type 2 diabetic patients (n = 175, 65 of whom were women) with stable glycemic control (variation in A1C <10% in the last 5 years) and without diagnosis of clinical macrovascular disease, inflammatory disease, malignancies, or pregnancy were studied. Fifty-three (20 of whom were women) nondiabetic subjects without previous clinical macrovascular disease and normal ABI (≥0.9) were recruited as control subjects.

Demographic, anthropometric, and clinical data and ABI were recorded in all subjects. Laboratory data were measured by commercially available assays, hsCRP by nephelometry, ultrasensitive PAPP-A using an enzyme-linked immunosorbent assay, and TNF-α and IL-6 concentrations using an enzyme chemiluminescence immumometric assay.

Continuous variables were expressed as means ± SD or median (interquartile range). Differences between groups were examined by Student’s t test or Mann-Whitney and correlation between variables by Pearson’s or Spearman’s tests as required. Multiple logistic regression analysis was performed.

Clinical and biochemical characteristics of all study subjects are shown in Table 1. PAPP-A levels were significantly higher in male than in female subjects in both groups (median [interquartile range] 1.04 [0.6–1.47] vs. 0.52 mIU/l [0.43–0.94], P = 0.025 in control subjects and 0.49 [0.23–0.93] vs. 0.35 mIU/l [0.13–0.63], P = 0.01 in diabetic patients).

Serum PAPP-A concentrations were significantly higher in control than in diabetic subjects (median [interquartile range] 0.73 [0.48–1.33] vs. 0.45 mIU/l [0.19–0.82], respectively, P < 0.0001) and correlated negatively with A1C (r = −0.2, P = 0.03). Diabetic patients were stratified according to mean ± SD values of A1C (<5.9, 5.9–8.2, and >8.2%). PAPP-A concentration was significantly lower in patients with A1C >8.2% (0.35 mUI/l [0.07–0.43]) compared with that in patients with A1C <5.9% (0.72 mUI/l [0.2–0.92], P < 0.03) and between 5.9 and 8.2% (0.56 mUI/l [0.15–0.83], P < 0.02) and control subjects (0.73 mUI/l [0.48–1.33], P < 0.001).

No differences in PAPP-A levels were observed when subjects with normocholesterolemia were compared with those with hypercholesterolemia (median [interquartile range] 0.6 [0.45–1.14] vs. 0.8 mUI/l [0.48–1.38], respectively) and with diabetic patients (0.6 [0.45–1.14] vs. 0.8 mUI/l [0.48–1.38]). On the other hand, when control subjects and diabetic patients with normocholesterolemia were compared, PAPP-A levels remained significantly higher in control subjects than in diabetic patients (0.6 [0.45–1.14] vs. 0.33 mUI/l [0.13–0.83], respectively, P = 0.04). We obtained the same results when control subjects and diabetic patients with hypercholesterolemia were compared (0.8 [0.48–1.38] vs. 0.44 mUI/l [0.22–0.78], P < 0.0001). Moreover, PAPP-A levels were similar in subjects treated with statins compared with those in untreated subjects in both groups.

No differences were observed in PAPP-A levels between diabetic patients with or without a history of diabetic vasculopathy (n = 25), abnormal ABI (n = 54), nephropathy (n = 42), or retinopathy (n = 59), and no relationship was found between plasma levels of PAPP-A and those of hemostasis parameters and inflammatory cytokines.

Multiple logistic regression analyses using PAPP-A as the dependent variable and age, BMI, and biochemical parameters as independent variables showed no associated factors other than A1C (P = 0.02) and glycemia (P = 0.04).

In the present study, PAPP-A levels were significantly lower in diabetic patients compared with those in age- and sex-matched control subjects without clinical macrovascular diseases, and, for the first time, a significant inverse correlation was found between PAPP-A and A1C, independent of other clinical and metabolic factors. The relationship between PAPP-A levels and A1C could reflect the influence of glycemic control on the regulation of PAPP-A expression. A possible hypothesis to consider is that PAPP-A may not be a good marker of vascular risk in chronic diseases such as diabetes. In fact, PAPP-A would be a modulator of proliferative local action of IGF-1 in atherosclerotic plaques (1–6). IGF-1 acts as a promoter of repair at damaged tissues (4,5,12), and increased PAPP-A levels may reflect a repaired mechanism against vascular damage (10).

In previous articles (13), diabetic patients with hypercholesterolemia showed higher PAPP-A levels than control subjects. We do not have an explanation for this disparity in our results; however, in that previous study, PAPP-A levels were measured in diabetic patients with a wide range of A1C, without a hypercholesterolemic control group.

No correlations were observed between PAPP-A and clinical and other biochemical data. In previous studies on this topic, there were discrepancies, and some authors have reported a relationship (2,10,14) between PAPP-A and hsCRP, while others have not (11).

The lack of an observed correlation between PAPP-A levels and IL-6 or TNF-α could reflect the complex interaction of multiple cytokines, and it is even possible that their exact role in PAPP-A expression is unknown. We found no previous reports on the relationship between plasma PAPP-A levels and the hemostatic parameters evaluated that were selected to globally identify coagulation or fibrinolysis activation in diabetic patients. The absolute PAPP-A serum concentrations found in our study could not be compared with those reported in other studies (2,10,11,15) owing to the different methods used for PAPP-A measurement (16).

Table 1—

Clinical, biochemical, and hemostatic characteristics of control and diabetic subjects

Control subjectsDiabetic patientsP
n 53 175 — 
    Male/female 33/20 110/65 NS 
Age (years) 63.3 ± 7.5 62 ± 7.9 NS 
Treatment (%)    
    Antidiabetes drugs — 39.3 — 
    Insulin — 27.7 — 
    Combined — 34.0 — 
    Statins 27 70 0.001 
ABI <0.9 — 30.8 — 
Hypercholesterolemia 69 84 0.02 
Current smoker 19 17 NS 
BMI (kg/m2) 29.5 ± 2.6 31.1 ± 4.7 0.002 
Waist circumference (cm) 98.7 ± 7.9 104.3 ± 11.8 0.002 
SBP (mmHg) 149 ± 19.5 146.7 ± 20.7 NS 
DBP (mmHg) 87.6 ± 9.3 79.1 ± 11.4 <0.0001 
Fasting plasma glucose (mg/dl) 81.3 ± 11.9 156.2 ± 46.9 <0.0001 
A1C (%) 5.2 ± 0.9 7.1 ± 1.1 <0.0001 
Cholesterol (mg/dl)    
    Total 210.6 ± 39 182.3 ± 39.7 <0.0001 
    HDL 48.3 ± 13.6 44.8 ± 13.6 NS 
    Non-HDL 162.2 ± 34.5 136.5 ± 36.8 <0.0001 
Triglycerides (mg/dl) 97 (73–153) 131 (88–193) 0.01 
Uric acid (mg/dl) 5.1 ± 1.5 5.8 ± 1.6 0.03 
hsCRP (mg/l) 3.47 (1.13–5.86) 3.15 (1.55–5.78) NS 
Fibrinogen (g/l) 3.2 ± 1.0 4.5 ± 1.1 <0.0001 
F1 + 2 (nmol/l) 0.81 ± 0.32 2.03 ± 0.65 <0.0001 
PAP (μg/l) 198.9 ± 90.2 207.1 ± 87.3 NS 
Control subjectsDiabetic patientsP
n 53 175 — 
    Male/female 33/20 110/65 NS 
Age (years) 63.3 ± 7.5 62 ± 7.9 NS 
Treatment (%)    
    Antidiabetes drugs — 39.3 — 
    Insulin — 27.7 — 
    Combined — 34.0 — 
    Statins 27 70 0.001 
ABI <0.9 — 30.8 — 
Hypercholesterolemia 69 84 0.02 
Current smoker 19 17 NS 
BMI (kg/m2) 29.5 ± 2.6 31.1 ± 4.7 0.002 
Waist circumference (cm) 98.7 ± 7.9 104.3 ± 11.8 0.002 
SBP (mmHg) 149 ± 19.5 146.7 ± 20.7 NS 
DBP (mmHg) 87.6 ± 9.3 79.1 ± 11.4 <0.0001 
Fasting plasma glucose (mg/dl) 81.3 ± 11.9 156.2 ± 46.9 <0.0001 
A1C (%) 5.2 ± 0.9 7.1 ± 1.1 <0.0001 
Cholesterol (mg/dl)    
    Total 210.6 ± 39 182.3 ± 39.7 <0.0001 
    HDL 48.3 ± 13.6 44.8 ± 13.6 NS 
    Non-HDL 162.2 ± 34.5 136.5 ± 36.8 <0.0001 
Triglycerides (mg/dl) 97 (73–153) 131 (88–193) 0.01 
Uric acid (mg/dl) 5.1 ± 1.5 5.8 ± 1.6 0.03 
hsCRP (mg/l) 3.47 (1.13–5.86) 3.15 (1.55–5.78) NS 
Fibrinogen (g/l) 3.2 ± 1.0 4.5 ± 1.1 <0.0001 
F1 + 2 (nmol/l) 0.81 ± 0.32 2.03 ± 0.65 <0.0001 
PAP (μg/l) 198.9 ± 90.2 207.1 ± 87.3 NS 

Data are means ± SD, percentages, or median (interquartile range). DBP, diastolic blood pressure; F1 + 2, prothrombin fragment 1 + 2; NS, nonsignificant; PAP, plasmin-antiplasmin complexes; SBP, systolic blood pressure.

View Large

This study was supported by a grant “Ajut a la recerca en diabetis Gonçal Lloveras i Vallès” from the Catalan Diabetes Association.

1.
Bayes-Genis A, Conover CA, Schwartz RS: The Insulin-like growth factor axis: a review of atherosclerosis and restenosis.
Circ Res
 
86
:
125
–130,
2000
2.
Bayes-Genis A, Conover CA, Overgaard MT, Bailey KR, Christiansen M, Holmes DR, Virmani R, Oxvig C, Schwartz RS: Pregnancy-associated plasma protein A as a marker of acute coronary syndromes.
N Engl J Med
 
345
:
1022
–1029,
2001
3.
Cosin-Sales J, Kaski JC, Christiansen M, Kaminski P, Oxvig C, Overgaard MT, Cole D, Holt DW: Relationship among pregnancy associated plasma protein-A levels, clinical characteristics, and coronary artery disease extent in patients with chronic stable angina pectoris.
Eur Heart J
 
26
:
2093
–2098,
2005
4.
Conti E, Andreotti F, Zuppi C: Pregnancy-associated plasma protein-A as predictor of outcome in patients with suspected acute coronary syndromes.
Circulation
 
109
:
e211
–e212,
2004
5.
Crea F, Andreotti F: Pregnancy associated plasma protein-A and coronary atherosclerosis: marker, friend, or foe?
Eur Heart J
 
26
:
2075
–2076,
2005
6.
Piñon P, Kaski JC: Inflammation, atherosclerosis and cardiovascular disease risk: PAPP-A, Lp-PLA2 and cystatin C: new insights or redundant information?
Rev Esp Cardiol
 
59
:
247
–258,
2006
7.
Reaven GM: The metabolic syndrome: is this diagnosis necessary?
Am J Clin Nutr
 
83
:
1237
–1247,
2006
8.
Resch ZT, Oxvig C, Bale LK, Conover CA: Stress-activated signaling pathways mediate the stimulation of pregnancy-associated plasma protein-A expression in cultured human fibroblasts.
Endocrinology
 
147
:
885
–890,
2006
9.
Resch ZT, Chen BK, Bale LK, Oxvig C, Overgaard MT, Conover CA: Pregnancy-associated plasma protein A gene expression as a target of inflammatory cytokines.
Endocrinology
 
145
:
1124
–1129,
2004
10.
Beaudeux JL, Burc L, Imbert-Bismut F, Giral P, Bernard M, Bruckert E, Chapman MJ: Serum plasma pregnancy-associated protein A: a potential marker of echogenic carotid atherosclerotic plaques in asymptomatic hyperlipidemic subjects at high cardiovascular risk.
Arterioscler Thromb Vasc Biol
 
23
:
e7
–e10,
2003
11.
Stulc T, Malbohan I, Malik J, Fialova L, Soukupova J, Ceska R: Increased levels of pregnancy-associated plasma protein-A in patients with hypercholesterolemia: the effect of atorvastatin treatment.
Am Heart J
 
146
:
1060
–1063,
2003
12.
Conti E, Carrozza C, Capoluongo E, Volpe M, Crea F, Zuppi C, Andreotti F: Insuline-like growth factor-1 as a vascular protective factor.
Circulation
 
110
:
2260
–2265,
2004
13.
Aso Y, Okumura K, Wakabayashi S, Takebayashi K, Taki S, Inukai T: Elevated pregnancy-associated plasma protein-A in sera from type 2 diabetic patients with hypercholesterolemia: associations with carotid atherosclerosis and toe-brachial index.
J Clin Endocrinol Metab
 
89
:
5713
–5717,
2004
14.
Heeschen C, Dimmeler S, Hamm CW, Fichtlscherer S, Simoons ML, Zeiher AM: Pregnancy-associated plasma protein-A levels in patients with acute coronary syndromes: comparison with markers of systemic inflammation, platelet activation, and myocardial necrosis.
J Am Coll Cardiol
 
45
:
229
–237,
2005
15.
Cosin-Sales J, Christiansen M, Kaminski P, Oxvig C, Overgaard MT, Cole D, Holt DW, Kaski JC: Pregnancy-associated plasma protein A and its endogenous inhibitor, the proform of eosinophil major basic protein (proMBP), are related to complex stenosis morphology in patients with stable angina pectoris.
Circulation
 
109
:
1724
–1728,
2004
16.
Fredericks S, Bertomeu-Gonzalez V, Petrovic I, Holt DW, Kaski JC: Comment on immunoassays developed for pregnancy-associated plasma protein-A (PAPP-A) in pregnancy may not recognize PAPP-A in acute coronary syndromes.
Clin Chem
 
52
:
1619
–1620,
2006

Published ahead of print at http://care.diabetesjournals.org on 28 August 2007. DOI: 10.2337/dc07-1092.

A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C Section 1734 solely to indicate this fact.

DIABETES CARE
2007